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Interventions: HT22 cells were subjected to pharmacologic induction of ferroptosis or mechanical stretch injury with and without administration of inhibitors of ferroptosis. Mice were subjected to sham or controlled cortical impact injury. Injured mice were randomized to receive vehicle or baicalein (12/15-lipoxygenase inhibitor) at 10–15 minutes postinjury.

Measurements and Main Results: Pharmacologic inducers of ferroptosis and mechanical stretch injury resulted in cell death that was rescued by prototypical antiferroptotic agents including baicalein. Liquid chromatography tandem-mass spectrometry revealed the abundance of arachidonic/adrenic-phosphatidylethanolamine compared with other arachidonic/adrenic acid-containing phospholipids in the brain. Controlled cortical impact resulted in accumulation of oxidized phosphatidylethanolamine, increased expression of 15-lipoxygenase and acyl-CoA synthetase long-chain family member 4 (enzyme that generates substrate for the esterification of arachidonic/adrenic acid into phosphatidylethanolamine), and depletion of glutathione in the ipsilateral cortex. Postinjury administration of baicalein attenuated oxidation of arachidonic/adrenic acid-containing-phosphatidylethanolamine, decreased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells in the hippocampus, and improved spatial memory acquisition versus vehicle.

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Supported, in part, by National Institutes of Health grants (NS061817, NS076511, AI068021, and NS079061).

Drs. Yang, Mayer, Kochanek, Dixon, Kagan, and Bayir received support for article research from the National Institutes of Health (NIH). Dr. Kochanek’s institution received funding from the NIH; he received funding from Society of Critical Care Medicine (Editor-in-Chief of Pediatric Critical Care Medicine) and from serving as an expert witness and a visiting professor/grand rounds speaker (travel/compensation); and he disclosed other funding separate from that reported in this study by both the NIH, the U.S. Department of Defense, and the state of Pennsylvania. Dr. Kagan disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest.